PROJECT SUMMARY Preclinical, clinical, and epidemiological studies have consistently revealed sex- and gender-related differences in substance use and the development of substance use disorders. Many of these sex differences can be attributed to gonadal hormones, and the effects of ovarian hormones across the estrous/menstrual cycle have been well documented for cocaine, methamphetamine, and other stimulants. Far fewer studies have examined the role of androgen hormones on drug sensitivity, and relatively few studies have examined the role of ovarian hormones on the self-administration of heroin and other opioids. This represents a limitation of the existing literature, given evidence that gonadal hormones alter sensitivity to the abuse-related effects of opioids in a manner very differently from the way they alter sensitivity to the effects of stimulants. The scientific objective of the proposed project is to characterize the effects of ovarian and androgen hormones on heroin self-administration in sexually mature male and female rats, while identifying hormonally based treatment interventions for opioid use disorders. To this end, Aim 1 will examine the effects of exogenous estradiol, progesterone, and their combination on heroin self-administration in gonadectomized male and female rats. Aim 2 will examine the role of endogenous ovarian hormones in the suppression of heroin self-administration during proestrus through receptor-selective antagonists. Aim 3 will examine the effects of exogenous estradiol and progesterone on heroin self-administration in gonadally intact female rats. Aim 4 will examine the effects of exogenous testosterone on heroin self-administration in gonadectomized male and female rats. Finally, Aim 5 will examine the effects of an androgen steroid inhibitor on heroin self-administration in gonadally intact male rats. The ultimate goal of these studies is to better predict sex-related differences in opioid use disorders and to identify novel and sex-specific treatment interventions for opioid abuse and addiction.